Melatonin MT₁ and MT₂ receptor ligands have been vigorously explored for the last 4 decades. Inspection of approximately 80 publications in the field revealed that most melatonergic ligands were structural analogues of melatonin combining three essential features of the parent compound: an aromatic ring bearing a methoxy group and an amide side chain in a relative arrangement similar to that present in melatonin. While several series of MT₂‐selective agents—agonists, antagonists, or partial agonists—were reported, the field was lacking MT₁‐selective agents. Herein, we describe various approaches toward the development of melatonergic ligands, keeping in mind that most of the molecules/pharmacophores obtained were essentially melatonin copies, even though diverse tri‐ or tetra‐cyclic compounds were explored. In addition to lack of structural diversity, only few studies examined the activity of the reported melatonergic ligands in vivo. Moreover, an extensive pharmacological characterization including biopharmaceutical stability, pharmacokinetic properties, specificity toward other major receptors to name a few remained scarce. For example, many of the antagonists described were not stable in vivo, were not selective for the melatonin receptor subtype of interest, and were not fully characterized from a pharmacological standpoint. Indeed, virtual screening of large compound libraries has led to the recent discovery of potent and selective melatonin receptor agonists and partial agonists of new chemotypes. Having said this, the melatonergic field is still lacking subtype‐selective melatonin receptor antagonists “active” in vivo, which are critical to our understanding of melatonin and melatonin receptors’ role in basic physiology and disease.

The various physiological actions of the neurohormone melatonin are mediated mainly by two G-protein-coupled MT1 and MT2 receptors. The melatoninergic drugs on the market, ramelteon and agomelatine, as well as the most advanced drug candidates under clinical evaluation, tasimelteon and PD-6735, are high-affinity nonselective MT1 and MT2 agonists. However, exploring the exact physiological role of the MT1 and MT2 melatonin receptors requires subtype selective MT1 and MT2 ligands. This review covers novel melatoninergic agonists and antagonists published since 2010, focusing on high-affinity and subtype selective agents. Additionally, compounds not mentioned in the previous review articles and ligands selective for the MT3 binding site are included.